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doi:10.1093/annonc/mds223
incidence and epidemiology ovarian tumors; other gonadal tumors arise from non-specic
ovarian cells.
Non-epithelial malignancies of the ovary account for 10% of Classication of GCTs is well established (Table 1). These
all ovarian cancers [1]. Germ cell tumors (GCTs) are tumors recapitulate the steps of development, from
diagnosed principally in the rst two decades of life, whereas undifferentiated germ cells to adult tissues. The primitive
sex cord-stromal tumors (SCSTs) are more common in adult GCTs, composed of undifferentiated germ cells and tumors
women (granulosa adult type has an average age at diagnosis with extra-embryonic differentiation, are all malignant.
clinical practice
of 50 years, 90% of juvenile type occurs in pre-pubertal girls Teratomas are the most common GCTs; most of them are
guidelines
and Sertoli-Leydig occurs mainly in women younger than 40 composed of mature tissues and are benign (dermoid cysts). In
years). The yearly adjusted incidence rate is 3.7/1 000 000 and immature teratomas, embryonic tissues represent the
2.1/1 000 000 women for GCTs and SCSTs, respectively [2]. malignant potential and grading is prognostically relevant.
Other rare malignant GCTs represent a heterogeneous group
diagnosis and pathology/molecular including somatic cancers arising in dermoids and some
biology monodermal teratomas [5].
Primitive GCTs and immature teratomas are chemosensitive
The initial symptoms and signs of non-epithelial ovarian and susceptible to fertility-sparing surgery. Because of their
tumors are usually a subacute pelvic pain and feeling of pelvic chemosensitivity and of the increasing adoption of fertility-
pressure because of a pelvic mass and menstrual irregularities. sparing surgery, the correct pathological diagnosis is essential.
Diagnostic work-up should include pelvic ultrasound, Owing to the rarity of these ovarian tumors, a histological
abdomino-pelvic computed tomography (CT-scan) and chest second opinion of expert pathologist/s should always be
X-ray. In young patients, serum human chorionic considered [level III]. Diagnosis can be made on conventional
gonadotropin (hCG), -fetoprotein (AFP) titers and lactate histologic material; given the multiplicity of morphological
dehydrogenase (LDH), complete blood count and liver and features, immunohistochemical markers (Table 2) and
renal function tests should be carried out. Inhibin is secreted chromosome 12p uorescence in situ hybridization can be
by granulosa cell tumors and could be a useful marker for this used to conrm the diagnosis in difcult cases. Salla4 and
disease [3]. In case of suspected gonadoblastomas, a OCT3/4 are widely used and more recently expression of SOX2
preoperative karyotype should be obtained on all pre-menarche in embryonal carcinoma and primitive neuroectoderm of
girls because of the propensity of these tumors to arise in teratoma has been recognized [6].
dysgenetic gonads [4]. Sex cord-stromal and steroid cell tumors constitute a
Primary non-epithelial tumors of the ovary arising from the heterogeneous group of tumors (Table 3) and vary in their
cells specic to the ovary (germ cells, granulosa cells, theca capacity to produce clinically signicant amounts of steroid
cells, stromal broblasts and steroid cells) are the most typical hormones. Those with sex cord elements are malignant, with
granulosa cell tumors being the most frequent histological type.
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Ofce,Via Neoplasms of pure ovarian stroma are mostly benign, >50%
L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; of them being bromas. Unlike GCTs, SCSTs and steroid cell
E-mail: clinicalguidelines@esmo.org
tumors occur over a wide range of age and many are found in
Approved by the ESMO Guidelines Working Group: October 2008, last update June peri and post-menopausal women; however, for specic tumor
2012. This publication supersedes the previously published versionAnn Oncol 2010; types, the age range is often more limited. Since patients are
21 (Suppl 5): v31v36.
The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
Annals of Oncology clinical practice guidelines
Table 1. Classication of germ cell tumor (GCTs) A subset of SCSTs is typically negative for FOXL2 on
immunostaining (retiform or poorly differentiated SLCTs), but
Primitive GCTs these tumors usually express a-inhibin and/or calretinin.
Dysgerminoma Among rare tumors including non-specic tumors of the
Yolk sac tumor ovary, the most frequent is small-cell carcinoma of
Embryonal carcinoma hypercalcemic type; it is the most common form of
Others undifferentiated carcinoma <40 years of age and the most
Mixed GCTs (specify components) common ovarian tumor associated with hypercalcemia. This
Biphasic or triphasic teratoma tumor is typically unilateral and should be differentiated from
Immature teratoma primitive GCTs and granulosa cell tumor.
Mature teratoma
Monodermal teratoma and somatic-type tumors associated with teratoma
sensitivity to chemotherapy, also advanced stage diseases can advanced stages and recurrences
have good prognosis. GCTs. Fertility-sparing surgery should be considered also in
advanced stage disease with a cure rate of > 95%. Patients
should undergo debulking surgery to remove as much gross
tumor as possible, but without major extensive procedures
treatment plan because of the high chemo-sensitivity of these tumors.
early stages Platinum-based regimens have been the treatment of choice
GCTs. The majority of GCTs (60%70%) are diagnosed at an over the past decade and the BEP regimen is the most widely
early stage. Stage I patients have an excellent prognosis with used platinum-based chemotherapy [16, 17]. The optimal
long-term disease free status in >90% of cases. Stage IA pure duration of therapy is still under debate; generally, three cycles
dysgerminoma can be treated with surgery only. The of BEP in completely resected disease and four to ve cycles
recurrence rate in this group of patients is relatively low (15% (bleomycin should be omitted to reduce the risk of lung
25%) and they can be successfully treated at the time of relapse toxicity) for patients with macroscopic residual disease seem
with a high likelihood of cure (Figure 1). appropriate [III, A]. Dysgerminomas are very sensitive to
Patients with Stage IA grade 1 immature teratoma do not radiotherapy; however, its use is limited to selected cases
require further adjuvant chemotherapy after adequate surgical because of the negative impact on fertility.
staging [13]. The need for adjuvant chemotherapy in stage IA In patients, previously treated with platinum, who have
G2-G3 and IB-IC is still controversial. Some published data relapsed after a disease-free interval >6 months ( platinum-
indicate that all grades of immature teratoma can be managed sensitive relapse), ifosfamide/platinum (IP) with or without
with close surveillance after fertility-sparing surgery (III, A), paclitaxel (P; Taxol) should be considered as second-line
reserving chemotherapy for those cases in which post-surgery treatment. Further active chemotherapy regimens include:
recurrence is documented [14]. However, this policy is not vinblastineifosfamidecisplatinum (VeIP), cisplatin,
universally accepted. vinblastine and bleomycin (PVB). Patients resistant to a
Overall, the role of chemotherapy in stage IA to B non- cisplatin-based combination may receive vincristine
dysgerminomatous ovarian GCTs remains controversial: a actinomycin Dcyclophosphamide (Cytoxan) [VAC] or
surveillance policy has been proposed by Charing Cross paclitaxelgemcitabine as salvage therapy [16].
Hospital and Mount Vernon Hospital groups in this subset of The role of secondary cytoreductive surgery in patients with
patients [15]. Data from the English literature show that the recurrent or progressive ovarian GCTs remains controversial. It
most used combination is bleomycin, etoposide and cisplatin may have some benets for a selected group of patients,
(BEP) [III, A].
Figure 1 Management of germ cell tumors (GCTs) of the ovary. X = suggested, * Properly surgical staged, (X) = suggested by some authors, = no therapy.
Figure 2 Management of sex cord stromal tumors (SCSTs) of the ovary. X = suggested, = no therapy.
Diagnosis and pathology/molecular Diagnostic work-up should include pelvic ultrasound, abdomino-pelvic computed tomography (CT-scan) and
biology chest X-ray
In young patients, human chorionic gonadotropin (hCG), -fetoprotein (AFP) titers and lactate dehydrogenase
(LDH), complete blood count, and liver and renal function tests should be carried out
In case of suspected gonadoblastomas, a preoperative karyotype should be obtained on all pre-menarche girls
In primitive germ cell tumors (GCTs) and immature teratomas, histological second opinion by expert
pathologist(s) should always be considered. Diagnosis can be made on conventional histologic material
Neoplasms of pure ovarian stroma: in morphologically ambiguous cases, an immunopanel of a-inhibin,
calretinin and FOXL2, plus mutational analysis for FOXL2 (402C-G), is useful to conrm granulosa cell tumor
of adult type
Staging and risk assessment Surgical approach can be carried out through open route or, in selected cases, by laparoscopy and robotics
A careful examination of the abdominal cavity is required
Staging procedure includes infracolic omentectomy, biopsy of the diaphragmatic peritoneum, paracolic gutters,
pelvic peritoneum and peritoneal washings
Node dissection should be carried out only in the cases with evidence of nodal abnormality
For SCSTs retroperitoneal evaluation is not mandatory
An endometrial curettage must be carried out to rule out concomitant uterine cancers in patients with GCTs
Unilateral salpingo-oophorectomy with preservation of the contralateral ovary and the uterus is considered an
adequate surgical treatment for patients with GCTs. This should be considered even in advanced disease
because of the sensitivity of the tumor to chemotherapy. No systematic ovarian biopsy is necessary when the
contralateral ovary is macroscopically normal
Conservative surgery seems to be the appropriate approach in young patients also for stage I disease SCSTs
In postmenopausal women and in patients with advanced stage disease or with bilateral ovarian involvement,
abdominal hysterectomy and bilateral salpingo-oophorectomy should be carried out with careful surgical staging
Early-stage GCTs: treatment plan Stage IA pure dysgerminoma can be treated with surgery only
Patients with Stage IA grade 1 immature teratoma do not require further adjuvant chemotherapy after adequate
surgical staging (14)
The need for adjuvant chemotherapy in stage IA G2-G3 and IB-IC is still controversial. Some data indicate that
all grades of immature teratoma can be managed with close surveillance after fertility-sparing surgery, reserving
chemotherapy for cases in which post-surgery recurrence is documented
Advanced stage and recurrent GCTs: Patients should undergo debulking surgery to remove as much gross tumor as possible, but without major
treatment plan extensive procedures
Platinum-based regimens are the treatment of choice with bleomycin, etoposide and cisplatin (BEP) regimen the
most widely used, generally, three cycles of BEP in completely resected disease and four to ve cycles
(bleomycin should be omitted to reduce the risk of lung toxicity) for patients with macroscopic residual disease
In patients, previously treated with platinum, relapsed after a disease-free interval >6 months (platinum-
sensitive relapse), combinations with platinum should be considered
Patients resistant to a cisplatin-based combination may receive VAC or paclitaxelgemcitabine as salvage therapy
Targeted agents either alone or in combination could represent therapeutic options, but their role must be
evaluated in prospective studies
Early-stage SCSTs: treatment plan Stage IA granulosa cell tumor disease has an excellent prognosis after surgery alone and does not require
adjuvant therapy. Some authors would suggest adjuvant therapy for stage IC patients with high mitotic index, in
this case platinum-based chemotherapy is the treatment of choice
BEP is the most commonly used regimen. Alternative chemotherapy options include: etoposide plus cisplatin;
cyclophosphamide, doxorubicin and cisplatin; paclitaxel and carboplatin; or platinum agent alone
Sertoli-Leydig cell tumors: postoperative adjuvant chemotherapy should be considered for patients with stage I
poorly differentiated or heterologous elements
Advanced stage and recurrent SCSTs: Debulking surgery remains the most effective treatment of metastatic or recurrent granulosa cell tumor.
treatment plan Platinum-based chemotherapy is currently used for patients with advanced stage SCSTs or recurrent disease
BEP regimen for 3 cycles or carboplatin/paclitaxel is recommended for adjuvant postoperative chemotherapy
and patients with recurrent SCSTs
Patients with steroid cell tumors, with tumors that are pleomorphic, have an increased mitotic count, are large,
or are at an advanced stage should be treated with additional postoperative platinum-based chemotherapy;
either BEP if not previously used or a taxaneplatinum combination
Response to gonadotropin-releasing hormone agonists, tamoxifen, progestins and aromatase inhibitors has been
reported
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